EP0876818B1 - Wirkstoff zur behandlung neurodegenerativer störungen - Google Patents

Wirkstoff zur behandlung neurodegenerativer störungen Download PDF

Info

Publication number
EP0876818B1
EP0876818B1 EP96935637A EP96935637A EP0876818B1 EP 0876818 B1 EP0876818 B1 EP 0876818B1 EP 96935637 A EP96935637 A EP 96935637A EP 96935637 A EP96935637 A EP 96935637A EP 0876818 B1 EP0876818 B1 EP 0876818B1
Authority
EP
European Patent Office
Prior art keywords
treatment
weeks
patients
pyrido
indole
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP96935637A
Other languages
English (en)
French (fr)
Other versions
EP0876818A2 (de
EP0876818A4 (de
Inventor
Inc Selena Pharmaceuticals
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medivation Neurology Inc
Original Assignee
Inc Selena Pharmaceuticals
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Inc Selena Pharmaceuticals filed Critical Inc Selena Pharmaceuticals
Priority to SI9630572T priority Critical patent/SI0876818T1/xx
Publication of EP0876818A2 publication Critical patent/EP0876818A2/de
Publication of EP0876818A4 publication Critical patent/EP0876818A4/de
Application granted granted Critical
Publication of EP0876818B1 publication Critical patent/EP0876818B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/006—Biological staining of tissues in vivo, e.g. methylene blue or toluidine blue O administered in the buccal area to detect epithelial cancer cells, dyes used for delineating tissues during surgery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention pertains to the use of chemical compounds in medicine, more specifically, to the use of the compounds selected from hydrogenated pyrido[4,3-b]indoles for the treatment of neurodegenerative diseases, and especially Alzheimer's disease (AD), due to the discovery of new properties intrinsic to these compounds.
  • chemical compounds selected from hydrogenated pyrido[4,3-b]indoles for the treatment of neurodegenerative diseases, and especially Alzheimer's disease (AD), due to the discovery of new properties intrinsic to these compounds.
  • AD Alzheimer's disease
  • tacrine hydrochloride which is 9-amino-1,2,3,4-tetrahydroacridine hydrochloride represented by the formula (A):
  • the mechanism of action of the said agent involves inhibiting choline esterase (Volger B.W. "Alternatives in the treatment of memory loss in patient with Alzheimer's disease. (Clinical Pharmacy. 1991 June 10 (6): 447 - 56).
  • tacrine is an analogue of the world famous physostigmine and is a traditional anticholine esterase agent
  • the treatment with tacrine is not always effective. Besides, tacrine tends to cause undesirable side-effects.
  • EAA neuromediatory excitatory amino acids
  • NMDA N-methyl-D-aspartate
  • ⁇ -amyloid is a neurotoxic factor inducing neurodegenerative processes in the neurones.
  • ⁇ -Amyloid is present in the neurotic plaques abundantly located on the surface of the brain of the patients suffering from Alzheimer's disease (Prelli et al., - J.Neurochem., 1988, v.51, p.648; Yanuer et al., - Science, 1990, v.250, p.279).
  • ⁇ -amyloid significantly enhances the excitotoxic effect of glutamate which is effected through the NMDA-receptor system (Koh et al., Brain Res., 1990, v.533, p.315; Mattson et al., - J. Neurosci., 1992, v. 12, p.376).
  • glutamate mediator concentrations nontoxic under normal conditions become toxic for neurones under conditions of the developing ⁇ -amyloid dose and cause their death.
  • the search for effective antagonists of the brain NMDA-receptors capable of preventing the realization of the neurotoxic effect of EAA appears to be an original and promising approach to creation of neuroprotectors of a wide spectrum of activity including agents which can prevent the development of Alzheimer's disease and be useful for treatment of such diseases as Alzheimer's disease (Maragos W.F. et al., Trends Neurosci.,1987, No. 10, p.65).
  • a well known NMDA receptor antagonist is 2-amino-5-phosphonovaleric acid (AP5) (Evans et al., Brit. J. Pharmacol., 1982, v.75, p.65).
  • AP5 2-amino-5-phosphonovaleric acid
  • An intensive search for and trials of the agents having the anti-NMDA properties is currently under way for treatment of said disease. However, such agents are actually not available in clinics thus far.
  • the object of the invention is to provide compounds having a high anti-NMDA activity and producing no side- and toxic effects.
  • the inventors have carried out large-scale investigations of some known compounds which are tetra - and hexahydro-1H-pyrido[4,3-b]indole derivatives manifesting a wide spectrum of biological activity.
  • antihistamine activity OS-DE NN 1.813 229, December 6, 1968; 1.952.80, October 20, 1969
  • central depressive and antiinflammatory activity USP No.3 718.657 December 13, 1970
  • neuroleptic activity Herbert C.A., Plattner S.S., Wehch W.N. - Mol.Pharm.
  • hevotroline (8-fluoro-2)(3-(3-pyridyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole dihydrochloride) is an antipsychotic and anxiolytic agent (Abou - Gharbi M., Patel U.R., Webb M.B., Moyer J.A., Ardnee T.H., J. Med. Chem., 1987, vol.30, p.1818-1823).
  • the inventors have quite unexpectedly found that such properties are endowed for hydrogenated pyrido[4,3-b]indole derivatives. It has been found in particular, that a number of known hydrogenated pyrido[3,4-b]indole derivatives has NMDA antagonist properties, which makes them useful for treating neurodegenerative diseases, especially Alzheimer's disease.
  • the present invention relates to the use of a hydrogenated pyrido[4,3-b]indole derivative of formula (I); wherein either;
  • mice were treated with white non-inbred male mice of 20 - 24 g weight.
  • a solution of the test agent in 0.2 ml of 5% aqueous dimethylsulfoxide was injected intraperitoneally 40 minutes before the injection of NMDA into the lateral vehicle of the brain.
  • Mice had been prepared beforehand for the experiment: a skin flap on the head was removed under ether anestesia and a hole was bored in the skull by a fine drill.
  • 0.1 ⁇ g of NMDA in a volume of 1.4 ⁇ l was injected with a microsyringe.
  • the microsyringe needle was immersed to a depth of 2.5 mm.
  • the wound was treated with a 2% novocaine solution.
  • the mice showed signs of pain disturbance.
  • the accuracy of NMDA injection was monitored by injection of methylene blue. Two to 4 hours after the operation, the mice were used for a pharmacological experiment.
  • the animals inoculated with a saline solution were used as control.
  • the injection of NMDA into the lateral ventricle in a dose of 0.1 ⁇ g per mouse caused run, jumps, convulsions and then the death of the animals.
  • the preinjection of the test substances prevented the development of convulsions and death of the animals.
  • the ED 50 value (the dose of the agent preventing the development of convulsions and the death of 50% of the animals) was determined by a probit-analysis method (Litchfild J.T., Wicoxon F.J. - Pharmacol.Exp.Therap., 1949, v. 96. p. 99-114).
  • the compounds according to the invention have an anti-NMDA activity expressed as ED 50 in the range of 16 - 45 mg/kg by intraperitoneal inoculation, i.e. in the pharmacologically acceptable range, and do not show any appreciable neurotoxic effect in the investigated doses.
  • the marked NMDA-antagonist properties found in the compounds of formula (I) permit a conclusion on the potential usefulness of the said compounds in the treatment of neurodegenerative diseases, and in particular, Alzheimer's disease.
  • the “dimebon” agent (compound No.10) which is used in medicine as an antiallergic agent (Inventor's Certificate No. 1138164, IP Class A61K 31/47,5, C07 D 209/52, published on February 7, 1985) was also clinically tested as an agent for treatment of Alzheimer's disease.
  • the carbidine agent (compound No.4) is less suitable for preliminary clinical tests due to its obvious psychotropic effect capable of masking some manifestations of positive treatment results. Dimebon is non-toxic and does not show any negative side-effects.
  • the test was carried out under the direct supervision by two of the inventors, namely E.E. Bukatina and V.Grigorieva in 14 patients who agreed to take part in the tests, 13 of whom lived in boarding house for senile persons and one patient lived with her family.
  • Alzheimer's disease was diagnosed on the basis of criteria ICD-10 NINCDS ADRDA.
  • Alzheimer's disease which had started before the admission to the boarding house.
  • progressive decline of memory was noted in the boarding house almost 2 years after her admission.
  • CT computer tomography
  • Dimebon in the form of tablets (comprising 10 mg of dimebon, 30 mg of lactose, 5 mg of magnesium stearate was prescribed for oral administration in a dose of 0.02 g three times a day.
  • the patients living in the boarding house received dimebon for 58 days.
  • the 0 score indicates the poorest result; on the contrary, according to the inventors' scale, the 0 score indicates the absence of a symptom 4 score indicates the greatest manifestation thereof.
  • the degree of disturbance of some function proved to be between the two evaluation indices, the value was of intermediate type, e.g. 0.5, 1.5, or the like.
  • the patients had been independently examined by two doctors who used the inventors' scale. The examination during the treatment was carried out by the doctors using both the scales.
  • the evaluation according to all the inventors' scale points during all the tests and their variations during the treatment with dimebon are given in the Appendix.
  • the degree of the disturbance if the cognitive functions was determined by a sum of evaluations according to the first 5 scale points reflecting the condition of memory, orientation and relation with the reality.
  • the disturbance of speech was dealt with separately and was determined by a sum of evaluations according to items 6b-6d. No disturbances of articulation (item 6a) corresponding to peculiar disturbances of speech functions in Alzheimer's disease were observed in any cases.
  • test results reflected the condition of the patients a the time of the examination. Any changes in the metal state observed in the interval between the tests and disappearing by the moment of examination according to the scale described in the section "Clinical Observations".
  • the statistical data processing was carried out by means of Student's t-test and Fisher's "Fi” criterion.
  • Table 3 The test results of 7 patients with relatively mild dementia are presented in Table 3. This group included the patients whose evaluation for each of the inventor's 5-point scale did not exceed 2.5 scores. In fact, only one of the patients had such score (observation 2) according to the 3rd scale point (memory for the past). All the other patients had lower scores.
  • Table 10 show some trend for improvement of speech functions during the period of dimebon administration, which was slightly more evident in the prolonged treatment.
  • the distribution pattern of the variations in items 6b-6d reflecting the condition of the speech functions is presented in Table 12.
  • Psychopathic-like symptoms in all 7 patients who suffered from them decreased significantly during the first 2 weeks or therapy. A distinct antidepressive effect of the agent was also observed in 8 patients. One of them (observation 10) showed no lower spirits during the test period, but, as the medical stuff reported, she had frequent disphorias which ceased during dimebon administration. Besides, the patient herself (dementia was not profound in this case) constantly emphasized that her mood improved during the treatment.
  • a pilot research of the effectiveness of dimebon in 14 patients suffering from Alzheimer's disease revealed definite positive effect of the agent on psychopatic-like and depressive manifestations.
  • the examinations carried out using Hazegawa's scale and the inventors scale revealed a significant improvement in cognitive functions especially in patients with mild dementia.

Claims (11)

  1. Verwendung eines hydrierten Pyrido[4,3-b]indolderivates der Formel (I)
    Figure 00460001
    worin
    Linie ----- eine Einfachbindung bedeutet und
    R1 Me bedeutet, R2 H bedeutet und R3 Me bedeutet und die Verbindung in der Form eines cis (±)-Isomers vorliegt, oder die Linie ----- eine Doppelbindung bedeutet und
    (i) R1 Et oder PhCH2 bedeutet und R2 und R3 H bedeuten,
    (ii) R1 und R2 Me bedeuten und R2 PhCH2 bedeutert,
    (iii) R1 Me bedeutet, R2 6-Me-3-Py-(CH2)2 bedeutet und R3 H bedeutet,
    (iv) R1 und R3 Me bedeuten und R2 6-Me-3-Py-(CH2)2 bedeutet,
    (v) R1 Me bedeutet, R2 H bedeutet und R3 H oder Me bedeutet,
    (vi) R1 Me bedeutet, R2 H bedeutet und R3 Br bedeutet,
    und von Salzen hiervon mit pharmakologisch verträglichen Säuren und von quaternären Derivaten bei der Herstellung eines Arzneimittels für die Verwendung bei der Behandlung neurodegenerativer Erkrankungen.
  2. Verwendung nach Anspruch 1, worin das Derivat der Formel (I) 2-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol ist.
  3. Verwendung nach Anspruch 1, worin das Derivat der Formel (I) 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol oder dessen Methyljodid ist.
  4. Verwendung nach Anspruch 1, worin das Derivat der Formel (I) cis-(±) 2,8-Dimethyl-2,3,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indol oder dessen Dihydrochlorid ist.
  5. Verwendung nach Anspruch 1, worin das Derivat der Formel (I) 2-Methyl-8-brom-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol oder dessen Hydrochlorid ist.
  6. Verwendung nach Anspruch 1, worin das Derivat der Formel (1) 2-Ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol ist.
  7. Verwendung nach Anspruch 1, worin das Derivat der Formel (I) 2-Benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol ist.
  8. Verwendung nach Anspruch 1, worin das Derivat der Formel (I) 2,8-Dimethyl-5-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol oder dessen Hydrochlorid ist.
  9. Verwendung nach Anspruch 1, worin das Derivat der Formel (I) 2-Methyl-5-[2-(6-methyl-3-pyridyl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol oder dessen Sesquisulfatmonohydrat ist.
  10. Verwendung nach Anspruch 1, worin das Derivat der Formel (I) 2,8-Dimethyl-5-[2-(6-methyl-3-pyridyl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol oder dessen Dihydrochlorid ist.
  11. Verwendung nach einem der vorausgehenden Ansprüche, wobei das Derivat der Formel (I) ein quaternäres Salz ist.
EP96935637A 1995-10-23 1996-10-23 Wirkstoff zur behandlung neurodegenerativer störungen Expired - Lifetime EP0876818B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
SI9630572T SI0876818T1 (en) 1995-10-23 1996-10-23 Agent for treating neuro-degenerative disorders

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
RU95118252A RU2106864C1 (ru) 1995-10-23 1995-10-23 Средство для лечения болезни альцгеймера
RU95118252 1995-10-23
PCT/RU1996/000306 WO1997015225A1 (fr) 1995-10-23 1996-10-23 Agent therapeutique contre les troubles neurodegeneratifs

Publications (3)

Publication Number Publication Date
EP0876818A2 EP0876818A2 (de) 1998-11-11
EP0876818A4 EP0876818A4 (de) 1999-01-07
EP0876818B1 true EP0876818B1 (de) 2002-12-18

Family

ID=20173218

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96935637A Expired - Lifetime EP0876818B1 (de) 1995-10-23 1996-10-23 Wirkstoff zur behandlung neurodegenerativer störungen

Country Status (11)

Country Link
US (6) US6187785B1 (de)
EP (1) EP0876818B1 (de)
AT (1) ATE229806T1 (de)
AU (1) AU7347496A (de)
CA (1) CA2269698C (de)
DE (1) DE69625518T2 (de)
DK (1) DK0876818T3 (de)
ES (1) ES2188793T3 (de)
HK (1) HK1016893A1 (de)
RU (1) RU2106864C1 (de)
WO (1) WO1997015225A1 (de)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012016707A2 (en) 2010-08-06 2012-02-09 Ratiopharm Gmbh Oral dosage form for the modified release of dimebolin
WO2012016708A1 (en) 2010-08-06 2012-02-09 Ratiopharm Gmbh Oral dosage form comprising dimebolin and donepezil

Families Citing this family (72)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2106864C1 (ru) 1995-10-23 1998-03-20 Николай Серафимович Зефиров Средство для лечения болезни альцгеймера
CA2363244C (en) * 2000-11-07 2006-06-13 Research In Motion Limited Multifunctional keyboard for a mobile communication device and method of operating the same
WO2004035580A1 (en) * 2002-10-21 2004-04-29 Aprea Ab Reactivation of wild type p53 in human tumour cells by a low molecular weight compound
RU2283108C2 (ru) * 2003-12-08 2006-09-10 Сергей Олегович Бачурин ГЕРОПРОТЕКТОР НА ОСНОВЕ ГИДРИРОВАННЫХ ПИРИДО(4,3-b) ИНДОЛОВ (ВАРИАНТЫ), ФАРМАКОЛОГИЧЕСКОЕ СРЕДСТВО НА ЕГО ОСНОВЕ И СПОСОБ ЕГО ПРИМЕНЕНИЯ
US20070179174A1 (en) * 2003-12-08 2007-08-02 Bachurin Sergei O Methods and compositions for slowing aging
FR2885905A1 (fr) * 2005-05-23 2006-11-24 Trophos Sa Nouveaux composes chimiques et leurs utilisations comme medicament
WO2007032699A1 (fr) * 2005-09-12 2007-03-22 Avdulov, Nikolai Andreevich Isomeres optiques (+) et (-) de trans-2,3,4,4a,5,9b-hexahydro-2,8-dimethyl-1h-pirido[4,3-b]indole
US20070117834A1 (en) * 2005-10-04 2007-05-24 David Hung Methods and compositions for treating Huntington's disease
RU2338537C2 (ru) * 2006-01-25 2008-11-20 Сергей Олегович Бачурин СРЕДСТВО ДЛЯ ЛЕЧЕНИЯ ШИЗОФРЕНИИ НА ОСНОВЕ ГИДРИРОВАННЫХ ПИРИДО(4,3-b)ИНДОЛОВ (ВАРИАНТЫ), ФАРМАКОЛОГИЧЕСКОЕ СРЕДСТВО НА ЕГО ОСНОВЕ И СПОСОБ ЕГО ПРИМЕНЕНИЯ
RU2317989C1 (ru) 2006-08-24 2008-02-27 Андрей Александрович Иващенко ЗАМЕЩЕННЫЕ АЗЕПИНО[4,3-b]ИНДОЛЫ, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, СПОСОБ ИХ ПОЛУЧЕНИЯ И ПРИМЕНЕНИЯ
AU2007297618A1 (en) * 2006-09-20 2008-03-27 Medivation Neurology, Inc. Hydrogenated pyrido [4,3-b] indoles such as dimebon for treating canine Cognitive Dysfunction Syndrome
US20100099700A1 (en) * 2006-09-20 2010-04-22 David Hung Hydrogenated pyrido (4,3-b) indoles for treating amyotrophic lateral sclerosis (als)
WO2008051599A2 (en) * 2006-10-27 2008-05-02 Medivation Neurology, Inc. Combination therapies for treating alzheimer's disease using i. a. dimebon and dolepezil
RU2329044C1 (ru) * 2006-11-16 2008-07-20 Андрей Александрович Иващенко Лиганды 5-ht6 рецепторов, фармацевтическая композиция, способ ее получения и лекарственное средство
RU2334514C1 (ru) * 2006-12-01 2008-09-27 Институт физиологически активных веществ Российской Академии наук СРЕДСТВО ДЛЯ УЛУЧШЕНИЯ КОГНИТИВНЫХ ФУНКЦИЙ И ПАМЯТИ НА ОСНОВЕ ГИДРИРОВАННЫХ ПИРИДО (4,3-b) ИНДОЛОВ (ВАРИАНТЫ), ФАРМАКОЛОГИЧЕСКОЕ СРЕДСТВО НА ЕГО ОСНОВЕ И СПОСОБ ЕГО ПРИМЕНЕНИЯ
RU2340342C2 (ru) * 2006-12-07 2008-12-10 Сергей Олегович Бачурин СРЕДСТВО ДЛЯ ЛЕЧЕНИЯ ОСТРЫХ И ХРОНИЧЕСКИХ НАРУШЕНИЙ МОЗГОВОГО КРОВООБРАЩЕНИЯ, В ТОМ ЧИСЛЕ ИНСУЛЬТА, НА ОСНОВЕ ГИДРИРОВАННЫХ ПИРИДО[4,3-b]ИНДОЛОВ (ВАРИАНТЫ), ФАРМАКОЛОГИЧЕСКОЕ СРЕДСТВО НА ЕГО ОСНОВЕ И СПОСОБ ЕГО ПРИМЕНЕНИЯ
WO2008112238A1 (en) * 2007-03-12 2008-09-18 Grey Fox Llc 2, 8-dimethyl-5- [2- (6-methylpyridin-3-yl) -ethyl] -2,3,4, 5-tetrahydro- ih- pyrido [4, 3 -b] indole dihydrochloride (dimebon) for the treatment of chronic pain
RU2334747C1 (ru) * 2007-04-05 2008-09-27 Андрей Александрович Иващенко ЗАМЕЩЕННЫЕ 2,3,4,5-ТЕТРАГИДРО-1Н-ПИРИДО[4,3-b]ИНДОЛЫ, СПОСОБ ИХ ПОЛУЧЕНИЯ И ПРИМЕНЕНИЯ
RU2327480C1 (ru) 2007-05-23 2008-06-27 Виктор Иванович Рощин Активный ингредиент лекарственного средства, лекарственное средство, фармацевтическая композиция и способ лечения больных с дементным синдромом
RU2338533C1 (ru) * 2007-06-28 2008-11-20 Сергей Олегович Бачурин СРЕДСТВО, ОБЛАДАЮЩЕЕ АНКСИОЛИТИЧЕСКИМ ДЕЙСТВИЕМ, НА ОСНОВЕ ГИДРИРОВАННЫХ ПИРИДО(4,3-b)ИНДОЛОВ (ВАРИАНТЫ), ФАРМАКОЛОГИЧЕСКОЕ СРЕДСТВО НА ЕГО ОСНОВЕ И СПОСОБ ЕГО ПРИМЕНЕНИЯ
EP2194980A4 (de) * 2007-09-20 2012-01-18 D2E Llc Fluor-haltige derivate von hydrogenierten pyrido[4,3-b]indolen mit neuroprotektiven und kognitionsverbessernden eigenschaften, herstellungsverfahren und verwendung
RU2007139634A (ru) * 2007-10-25 2009-04-27 Сергей Олегович Бачурин (RU) Новые тиазол-, триазол- или оксадиазол-содержащие тетрациклические соединения
TWI447117B (zh) * 2007-10-25 2014-08-01 Medivation Technologies Inc 新穎四環化合物
JP2011507835A (ja) * 2007-12-21 2011-03-10 アンドレイ・アレクサンドロビッチ・イワシェンコ α−アドレナリン受容体、ドーパミン、ヒスタミン、イミダゾリン及びセロトニン受容体のリガンド並びにその使用
RU2544856C2 (ru) 2008-01-25 2015-03-20 Сергей Олегович Бачурин НОВЫЕ ПРОИЗВОДНЫЕ 2,3,4,5-ТЕТРАГИДРО-1-ПИРИДО[4,3-b]ИНДОЛА И СПОСОБЫ ИХ ПРИМЕНЕНИЯ
CN102046625B (zh) 2008-03-24 2015-04-08 梅迪维新技术公司 桥连杂环化合物及其使用方法
BRPI0906244A2 (pt) * 2008-03-24 2015-06-30 Medivation Technologies Inc Composto, composição farmacêutica, método para tratar um distúrbio cognitivo, psicótico, mediado por neurotransmissores ou um distúrbio neuronal em um indivíduo, uso de um composto e kit
EP2272955B1 (de) * 2008-04-09 2015-08-26 Tokyo Metropolitan Institute of Medical Science Tdp-43-speicherzellmodell
RU2374245C1 (ru) * 2008-08-22 2009-11-27 Андрей Александрович Иващенко Лиганд с широким спектром одновременной рецепторной активности, фармацевтическая композиция, способ ее получения и лекарственное средство
EP2340254B8 (de) 2008-09-15 2014-05-21 Biovista, Inc. Zusammensetzungen und verfahren zur behandlung von epilepsie
US9625475B2 (en) 2008-09-29 2017-04-18 Abbvie Inc. Indole and indoline derivatives and methods of use thereof
EP2344505A2 (de) 2008-09-29 2011-07-20 Abbott Laboratories Indol- und indolinderivate sowie verwendungsverfahren dafür
BRPI0919948A2 (pt) 2008-10-31 2015-08-25 Madivation Technologies Inc Pirido[4,3-b]indois contendo porções rígidas
US8569287B2 (en) 2008-10-31 2013-10-29 Medivation Technologies, Inc. Azepino[4,5-B]indoles and methods of use
US20100137215A1 (en) * 2008-11-25 2010-06-03 Concert Pharmaceuticals Inc. Novel tetrahydro-1h-pyrido[4,3-b]indoles
CN107595841A (zh) 2009-01-09 2018-01-19 得克萨斯州大学系统董事会 前神经原性化合物
US9162980B2 (en) 2009-01-09 2015-10-20 Board Of Regents Of The University Of Texas System Anti-depression compounds
US9962368B2 (en) 2009-01-09 2018-05-08 Board Of Regents Of The University Of Texas System Pro-neurogenic compounds
US8362277B2 (en) 2009-01-09 2013-01-29 Board Of Regents Of The University Of Texas System Pro-neurogenic compounds
EP2396327A1 (de) 2009-02-11 2011-12-21 Sunovion Pharmaceuticals Inc. Inverse histamin-h3-agonisten und -antagonisten und verfahren zu ihrer verwendung
EP2236160A3 (de) 2009-03-31 2011-12-14 Sanovel Ilac Sanayi ve Ticaret A.S. Dimebolin enthaltende Zusammensetzungen mit modifizierter Freisetzung
EP2236159A3 (de) 2009-03-31 2011-12-07 Sanovel Ilac Sanayi ve Ticaret A.S. Dimebolin enthaltende Zusammensetzungen mit modifizierter Freisetzung
TR200903014A1 (tr) 2009-04-17 2010-11-22 Sanovel İlaç San. Ve Ti̇c. A.Ş. Oral yolla dağılan dimebolin bileşimleri.
CA2760516A1 (en) 2009-04-29 2011-02-17 Medivation Technologies, Inc. Pyrido[4,3-b]indoles and methods of use
US9255094B2 (en) 2009-04-29 2016-02-09 Medivation Technologies, Inc. Pyrido[4,3-B]indoles and methods of use
EP2480081A4 (de) 2009-09-23 2013-03-06 Medivation Technologies Inc Gebrückte heterocyclische verbindungen und verfahren zu ihrer verwendung
EP2480078A4 (de) 2009-09-23 2013-03-06 Medivation Technologies Inc Pyrido-[4,3-b-]indole und verwendungsverfahren dafür
CN102724875B (zh) 2009-09-23 2015-05-27 梅迪维新技术公司 吡啶并[3,4-b]吲哚化合物及其使用方法
WO2011039675A2 (en) 2009-09-30 2011-04-07 Pfizer Inc. Latrepirdine transdermal therapeutic dosage forms
WO2011039686A1 (en) 2009-09-30 2011-04-07 Pfizer Inc. Latrepirdine oral sustained release dosage forms
WO2011039670A1 (en) 2009-09-30 2011-04-07 Pfizer Inc. Novel forms of (2,8-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-3,4-dihydro-1h-pyrido[4,3-b] indole)
RU2428185C1 (ru) * 2009-12-29 2011-09-10 Учреждение Российской Академии Наук Институт Физиологически Активных Веществ Ран (Ифав Ран) ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ ДЛЯ ЛЕЧЕНИЯ НЕЙРОДЕГЕНЕРАТИВНЫХ ЗАБОЛЕВАНИЙ НА ОСНОВЕ ГИДРИРОВАННОГО ПИРИДО(4,3-b)ИНДОЛА, СПОСОБ ЕЕ ПОЛУЧЕНИЯ И ФАРМАКОЛОГИЧЕСКОЕ СРЕДСТВО НА ЕЕ ОСНОВЕ
TR201001117A1 (tr) 2010-02-15 2011-09-21 Sanovel İlaç San.Ve Ti̇c.A.Ş. Dimebolin ve memantin kombinasyonları
US9193728B2 (en) 2010-02-18 2015-11-24 Medivation Technologies, Inc. Fused tetracyclic pyrido [4,3-B] indole and pyrido [3,4-B] indole derivatives and methods of use
US9034865B2 (en) 2010-02-18 2015-05-19 Medivation Technologies, Inc. Pyrido [4,3-B] indole and pyrido [3,4-B] indole derivatives and methods of use
WO2011103485A1 (en) 2010-02-18 2011-08-25 Medivation Technologies, Inc. Fused tetracyclic pyrido[4,3-b]indole and pyrido[3,4-b]indole derivatives and methods of use
WO2011103430A1 (en) 2010-02-19 2011-08-25 Medivation Technologies, Inc. Pyrido[4,3-b]indole and pyrido[3,4-b]indole derivatives and methods of use
WO2012006419A2 (en) 2010-07-07 2012-01-12 Board Of Regents Of The University Of Texas System Pro-neurogenic compounds
RU2451686C1 (ru) * 2010-12-27 2012-05-27 Александр Васильевич Иващенко ЗАМЕЩЕННЫЕ ГИДРИРОВАННЫЕ ТИЕНО-ПИРРОЛО [3,2-c] ПИРИДИНЫ, ЛИГАНДЫ, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ И СПОСОБ ИХ ПРИМЕНЕНИЯ
US20140155384A1 (en) 2011-02-18 2014-06-05 Medivation Technologies, Inc. Compounds and methods of treating diabetes
US9035056B2 (en) 2011-02-18 2015-05-19 Medivation Technologies, Inc. Pyrido[4,3-b]indole and pyrido[3,4-b]indole derivatives and methods of use
AU2012254158B2 (en) 2011-02-18 2016-02-04 Medivation Technologies, Inc. Compounds and methods of treating diabetes
US9434747B2 (en) 2011-02-18 2016-09-06 Medivation Technologies, Inc. Methods of treating diabetes
DE102012003065A1 (de) * 2012-02-13 2013-08-14 Friedrich-Schiller-Universität Jena Neue bivalente Gammacarbolinderivate sowie deren Herstellung und Verwendung als Antidementiva
WO2013130422A1 (en) 2012-02-27 2013-09-06 Biovista, Inc. Compositions and methods for treating mitochondrial diseases
EP2887805A4 (de) * 2012-08-22 2016-08-17 Medivation Technologies Inc Verbindungen und verfahren zur behandlung von bluthochdruck
EP2887803A4 (de) 2012-08-24 2016-08-03 Univ Texas Pro-neurogene verbindungen
WO2014207241A1 (en) * 2013-06-28 2014-12-31 Alzprotect NEW Na-SUBSTITUTED CARBOLINE COMPOUNDS USABLE FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES
EP3068388A4 (de) 2013-11-11 2017-04-12 Board of Regents of the University of Texas System Nervenschützende verbindungen und verwendung davon
WO2015070237A1 (en) 2013-11-11 2015-05-14 Board Of Regents Of The University Of Texas System Neuroprotective chemicals and methods for identifying and using same
EP2918792A1 (de) * 2014-03-13 2015-09-16 Siemens Aktiengesellschaft Dampfkraftanlage mit Spindelleckdampfleitung
CN109535157B (zh) * 2018-12-03 2021-10-15 江苏科技大学 一种半蜡梅碱类似物、其合成方法及其用途

Family Cites Families (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU1138164A1 (ru) * 1963-04-25 1985-02-07 Shadurskij Konstantin S Антигистаминное средство "димебон
DE1813229A1 (de) 1967-12-08 1970-08-20 Sumitomo Chemical Co gamma-Carboline und ihre Salze und Verfahren zu ihrer Herstellung
US3743740A (en) * 1968-10-31 1973-07-03 I Zhukova 3,6-dimethyl - 1,2,3,4,4a,9a - hexahydro-ypsilon-carboline dihydrochloride for treating mental diseases
GB1276113A (en) 1969-10-17 1972-06-01 Nii Farmakologii I Khim 3,6-DIMETHYL 1,2,3,4a,9a-HEXAHYDRO-gamma-CARBOLINE DIHYDROCHLORIDE
DE1952800C3 (de) 1969-10-20 1974-04-18 Nautschno-Issledowatelskij Institut Farmakologii I Chimioterapii, Moskau 3,6-Dimethyl-l,2,3,4,4a,9a-hexahydro-gamma-carbolin-dihydrochlorid
US3718657A (en) * 1970-12-03 1973-02-27 Abbott Lab Certain-2-substituted-1,2,3,4-tetrahydro-beta or gamma carbolines
SE7414572L (de) * 1973-12-06 1975-06-09 Endo Lab
AR205452A1 (es) * 1973-12-06 1976-05-07 Endo Lab Metodo para preparar nuevos trans-2, 3, 4, 4a, 5, 9b-hexahidro-5-fenil-1h-pirido(4,3-b) indoles
US4174453A (en) * 1973-12-06 1979-11-13 Endo Laboratories, Inc. Trans-hexahydro-pyrido-indoles
SE441448B (sv) * 1977-05-23 1985-10-07 Pfizer Sett att framstella hexahydro-gamma-karbolinforeningar
US4636563A (en) * 1985-09-16 1987-01-13 American Home Products Corporation Antipsychotic γ-carbolines
GB8600783D0 (en) 1986-01-14 1986-02-19 Merck Sharp & Dohme N-methyl-d-aspartate receptor antagonists
US4801612A (en) * 1986-07-03 1989-01-31 Regents Of The University Of California Method of inhibiting inflammatory response
US4985256A (en) * 1988-04-27 1991-01-15 Bionix Corporation Methods for diagnosing, monitoring and controlling the onset and progression of certain dementias and impeding memory loss or improving impairment of memory
US6017957A (en) * 1989-08-08 2000-01-25 The United States Of America As Represented By The Department Of Health And Human Services Partial agonists of the strychnine insensitive glycine modulatory site of the N-methyl-D-aspartate receptor complex as neuropsychopharmacological agents
EP0424179A3 (en) 1989-10-20 1991-12-27 John William Olney Use of combined excitatory amino acid and cholinergic antagonists to prevent neurological deterioration
US5455279A (en) * 1991-04-19 1995-10-03 The Children's Medical Center Corporation Regimen method of mediating neuronal damage using nitroglycerine
US5319096A (en) * 1992-04-03 1994-06-07 Hoechst-Roussel Pharmaceuticals Inc. (1H-indol-1-yl)-2-(amino) acetamides and related (1H-indol-1-yl)-(aminoalkyl)amides, pharmaceutical composition and use
DE4212529A1 (de) * 1992-04-10 1993-10-14 Schering Ag Verwendung von µ-Carbolinen als nicht-kompetitive Glutamat-Antagonisten
US5248690A (en) 1992-07-07 1993-09-28 R. J. Reynolds Tobacco Company Method for treatment of neurodegenerative diseases
US6362160B1 (en) * 1993-06-30 2002-03-26 The Johns Hopkins University School Of Medicine Immunophilin-binding agents prevent glutamate neurotoxicity associated with vascular stroke and neurodegenerative diseases
US5587384A (en) * 1994-02-04 1996-12-24 The Johns Hopkins University Inhibitors of poly(ADP-ribose) synthetase and use thereof to treat NMDA neurotoxicity
US5849761A (en) * 1995-09-12 1998-12-15 Regents Of The University Of California Peripherally active anti-hyperalgesic opiates
RU2140417C1 (ru) 1995-10-17 1999-10-27 Институт физиологически активных веществ РАН Производные гидрированных пиридо(4,3-b)индолов, способы их получения, фармацевтическая композиция и способ лечения
RU2106864C1 (ru) * 1995-10-23 1998-03-20 Николай Серафимович Зефиров Средство для лечения болезни альцгеймера
US6391871B1 (en) * 1996-09-20 2002-05-21 John W. Olney Preventing neuronal degeneration in Alzheimer's disease
US5958919A (en) * 1996-09-20 1999-09-28 Washington University Treatment of presymptomatic alzheimer's disease to prevent neuronal degeneration
US6306909B1 (en) * 1997-03-12 2001-10-23 Queen's University At Kingston Anti-epileptogenic agents
US6379882B1 (en) * 1998-09-14 2002-04-30 Elan Pharmaceuticals, Inc. Method for selecting compounds for treating ischemia-related cellular damage
JP2003517023A (ja) * 1999-12-16 2003-05-20 バイオジェン インコーポレイテッド 中枢神経系の虚血性損傷または出血性損傷を、抗α４インテグリンアンタゴニストを用いて処置する方法
RU2283108C2 (ru) 2003-12-08 2006-09-10 Сергей Олегович Бачурин ГЕРОПРОТЕКТОР НА ОСНОВЕ ГИДРИРОВАННЫХ ПИРИДО(4,3-b) ИНДОЛОВ (ВАРИАНТЫ), ФАРМАКОЛОГИЧЕСКОЕ СРЕДСТВО НА ЕГО ОСНОВЕ И СПОСОБ ЕГО ПРИМЕНЕНИЯ

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012016707A2 (en) 2010-08-06 2012-02-09 Ratiopharm Gmbh Oral dosage form for the modified release of dimebolin
WO2012016708A1 (en) 2010-08-06 2012-02-09 Ratiopharm Gmbh Oral dosage form comprising dimebolin and donepezil

Also Published As

Publication number Publication date
HK1016893A1 (en) 1999-11-12
US20020115682A1 (en) 2002-08-22
US7071206B2 (en) 2006-07-04
DE69625518D1 (de) 2003-01-30
US20040044022A1 (en) 2004-03-04
US20060140866A1 (en) 2006-06-29
CA2269698A1 (en) 1997-05-01
WO1997015225A1 (fr) 1997-05-01
RU2106864C1 (ru) 1998-03-20
US6187785B1 (en) 2001-02-13
US20050096342A1 (en) 2005-05-05
AU7347496A (en) 1997-05-15
DE69625518T2 (de) 2003-09-04
EP0876818A2 (de) 1998-11-11
CA2269698C (en) 2007-09-18
US20010020028A1 (en) 2001-09-06
EP0876818A4 (de) 1999-01-07
ES2188793T3 (es) 2003-07-01
ATE229806T1 (de) 2003-01-15
DK0876818T3 (da) 2003-03-31

Similar Documents

Publication Publication Date Title
EP0876818B1 (de) Wirkstoff zur behandlung neurodegenerativer störungen
US11426419B2 (en) Compositions and methods for the repair of myelin
CN101987849B (zh) 治疗与年龄相关的黄斑变性(amd)的方法
JP2010507672A (ja) アルツハイマー病を治療するための方法および組み合わせ治療
US5693645A (en) Use of spiperone or spiperone derivatives as immunosuppressant agents
US20020048612A1 (en) GABA substrate and the use thereof for treating cognitive and emotional disorders
US5510381A (en) Method of treatment of mania and bipolar disorder
AU2004233587A1 (en) Use of a topical medicament comprising Riluzole
JP2021507945A (ja) 認知症を含む神経障害のための組成物および治療方法
JP2021507944A (ja) 運動ニューロン疾患を含む神経障害のための組成物および治療方法
US20230129151A1 (en) Compositions and methods for the treatment of myelin related and inflammation related diseases or disorders
JPH08510990A (ja) グリシンｎｍｄａレセプター複合体の機能的アンタゴニストによる認識の改良方法
JPH0354922B2 (de)
US5484788A (en) Buspirone as a systemic immunosuppressant
JP2006516629A (ja) 置換キノリンおよび置換ジフェニルスルホンを含有する組成物および方法
JPH0813741B2 (ja) 抗痴呆剤
CN101293831B (zh) 3-羟基脂肪酸及其衍生物在制备钙离子通道调节剂中的用途
JPH1179995A (ja) 多発性硬化症治療剤
US20110224300A1 (en) USE OF POTASSIUM 2-(a- HYDROXYPENTYL) BENZOATE IN THE MANUFACTURE OF MEDICAMENTS FOR PREVENTING AND/OR TREATING SENILE DEMENTIA
JPH05502446A (ja) 老人性痴呆症治療のためのグリシル―ｐ―アミノ―ピリジン
Kamath Study of Anticonvulsant effect of Simvastatin in Maximal Electroshock and Pentylenetetrazole Induced Seizure Model In Albino Mice
JP2003221337A (ja) 酢酸アミド誘導体を有効成分とする痴呆症治療剤
JPH0541603B2 (de)
JPH06505255A (ja) 皮膚病治療薬の調製へのテトラヒドロ−チエノピリドインドール誘導体の使用
JP2017155007A (ja) 自閉スペクトラム症改善用組成物

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19980525

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: LT PAYMENT 980525;LV PAYMENT 980525;RO PAYMENT 980525;SI PAYMENT 980525

A4 Supplementary search report drawn up and despatched

Effective date: 19981119

AK Designated contracting states

Kind code of ref document: A4

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

17Q First examination report despatched

Effective date: 20001221

RIC1 Information provided on ipc code assigned before grant

Free format text: 7A 61K 31/475 A, 7A 61P 25/28 B

RIC1 Information provided on ipc code assigned before grant

Free format text: 7A 61K 31/475 A, 7A 61P 25/28 B

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

RIC1 Information provided on ipc code assigned before grant

Free format text: 7A 61K 31/475 A, 7A 61P 25/28 B

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: SELENA PHARMACEUTICALS, INC

RIN1 Information on inventor provided before grant (corrected)

Inventor name: SELENA PHARMACEUTICALS, INC

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: LT PAYMENT 19980525;LV PAYMENT 19980525;RO PAYMENT 19980525;SI PAYMENT 19980525

REF Corresponds to:

Ref document number: 229806

Country of ref document: AT

Date of ref document: 20030115

Kind code of ref document: T

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

RIN2 Information on inventor provided after grant (corrected)

Free format text: ZEFIROV, NIKOLAI SERAFIMOVICH * AFANASIEV, ANDREI ZAKHAROVICH * AFANASIEVA, SVETLANA VASILIEVNA * BACHURIN, SERGEI OLEGOVICH * TKACHENKO, SERGEI EVGENIEVICH * GRIGORIEV, VLADIMIR VIKTOROVICH * JUROVSKAYA, MARINA ABRAMOVNA * CHETVERIKOV, VALERY PAVLOVICH * BUKATINA, ELIZAVETA EVGENIEVNA * GRIGORIEVA, IRINA VLADIMIROVNA

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REF Corresponds to:

Ref document number: 69625518

Country of ref document: DE

Date of ref document: 20030130

Kind code of ref document: P

Ref document number: 69625518

Country of ref document: DE

Date of ref document: 20030130

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: MICHELI & CIE INGENIEURS-CONSEILS

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20030400914

Country of ref document: GR

LTIE Lt: invalidation of european patent or patent extension

Effective date: 20021218

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2188793

Country of ref document: ES

Kind code of ref document: T3

ET Fr: translation filed
PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20030919

REG Reference to a national code

Ref country code: GB

Ref legal event code: 732E

REG Reference to a national code

Ref country code: FR

Ref legal event code: TP

REG Reference to a national code

Ref country code: CH

Ref legal event code: PUE

Owner name: MEDIVATION, INC.

Free format text: SELENA PHARMACEUTICALS, INC#167 SKYVIEW WAY#SAN FRANCISCO, CALIFORNIA 94131 (US) -TRANSFER TO- MEDIVATION, INC.#501 SECOND STREET, SUITE 211#SAN FRANCISCO, CA 94107 (US)

NLS Nl: assignments of ep-patents

Owner name: MEDIVATION, INC.

REG Reference to a national code

Ref country code: ES

Ref legal event code: PC2A

REG Reference to a national code

Ref country code: PT

Ref legal event code: PC4A

Free format text: MEDIVATION, INC. US

Effective date: 20040625

REG Reference to a national code

Ref country code: SI

Ref legal event code: IF

REG Reference to a national code

Ref country code: PT

Ref legal event code: PC4A

Owner name: MEDIVATION NEROLOGY, INC, US

Effective date: 20080808

REG Reference to a national code

Ref country code: GB

Ref legal event code: 732E

REG Reference to a national code

Ref country code: FR

Ref legal event code: TP

REG Reference to a national code

Ref country code: CH

Ref legal event code: PUE

Owner name: MEDIVATION NEUROLOGY, INC.

Free format text: MEDIVATION, INC.#201 SPEAR STREET, 3RD FLOOR#SAN FRANCISCO, CALIFORNIE 94105 (US) -TRANSFER TO- MEDIVATION NEUROLOGY, INC.#201 SPEAR STREET, 3RD FLOOR#SAN FRANCISCO, CA 94105 (US)

Ref country code: CH

Ref legal event code: PCOW

Free format text: MEDIVATION, INC.;201 SPEAR STREET, 3RD FLOOR;SAN FRANCISCO, CALIFORNIE 94105 (US)

REG Reference to a national code

Ref country code: ES

Ref legal event code: PC2A

REG Reference to a national code

Ref country code: SI

Ref legal event code: SP73

Owner name: MEDIVATION NEUROLOGY, INC.; US

Effective date: 20090702

NLS Nl: assignments of ep-patents

Owner name: MEDIVATION NEUROLOGY, INC.

Effective date: 20090616

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GR

Payment date: 20130927

Year of fee payment: 18

Ref country code: DK

Payment date: 20130925

Year of fee payment: 18

Ref country code: PT

Payment date: 20130423

Year of fee payment: 18

Ref country code: MC

Payment date: 20130927

Year of fee payment: 18

Ref country code: IE

Payment date: 20130926

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20130925

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 20131105

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20130924

Year of fee payment: 18

Ref country code: CH

Payment date: 20131029

Year of fee payment: 18

Ref country code: AT

Payment date: 20130925

Year of fee payment: 18

Ref country code: DE

Payment date: 20131031

Year of fee payment: 18

Ref country code: SE

Payment date: 20131007

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20131016

Year of fee payment: 18

Ref country code: NL

Payment date: 20131010

Year of fee payment: 18

Ref country code: BE

Payment date: 20131104

Year of fee payment: 18

Ref country code: FI

Payment date: 20131007

Year of fee payment: 18

Ref country code: ES

Payment date: 20131011

Year of fee payment: 18

REG Reference to a national code

Ref country code: PT

Ref legal event code: MM4A

Free format text: LAPSE DUE TO NON-PAYMENT OF FEES

Effective date: 20150423

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 69625518

Country of ref document: DE

REG Reference to a national code

Ref country code: NL

Ref legal event code: V1

Effective date: 20150501

REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

Effective date: 20141031

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141023

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141031

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 229806

Country of ref document: AT

Kind code of ref document: T

Effective date: 20141023

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20141023

REG Reference to a national code

Ref country code: GR

Ref legal event code: ML

Ref document number: 20030400914

Country of ref document: GR

Effective date: 20150505

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141031

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141024

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141031

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20150423

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141031

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20150501

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141023

Ref country code: FI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141023

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20150630

Ref country code: SI

Ref legal event code: KO00

Effective date: 20150610

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20150501

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141023

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141031

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141023

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20150505

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141023

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141031

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20151127

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141024